1. Field of the Invention
This invention relates to porphyrin-based compounds modified with a chromophore useful in photodynamic therapy (“PDT”), particularly multi-photon PDT, and methods of using the compounds in PDT and related applications. In particular, a method of treating a tumor disease or a tumor by contacting an therapeutically effective amount of the porphyrin-based compound and irradiating the modified porphyrin with sufficient radiation to produce singlet oxygen is disclosed. Preferably the modified porphyrin simultaneously absorbs two photons of radiation which radiation is preferably is in a range of about 700 nm to about 1300 nm.
2. Discussion of the Related Art
Photodynamic therapy is an accepted treatment of tumors, as well as age related macular degeneration. PDT is initiated by introducing a photosensitizer agent into a subject's blood stream. After an appropriate time interval (usually tens of hours), the photosensitizer is activated by shining a visible light, usually a red color laser beam, at the tumor's location.
PDT employs the special ability of some porphyrin and porphyrin-like photosensitizers to accumulate in pathologic cells, and to transfer, upon or subsequent to radiation, absorbed photon energy to naturally occurring oxygen molecules in blood and tissue. Photophysical processes constituting PDT using porphyrins agents are summarized in the energy level diagram shown in FIG. 1.
In its classical implementation, absorption of one photon of visible wavelength takes a photosensitizer molecule into a short-lived excited state, S1, with energy of 170-190 kJ mol−1, which corresponds to an illumination wavelength of about 620 to 690 nm. After a few nanoseconds, the porphyrin converts into a triplet state, T1, by an intersystem crossing (ISC) mechanism with energy of 110-130 kJ mol−1 and a much longer lifetime, on the order of milliseconds. From this triplet state, energy is transferred to omnipresent oxygen molecules by switching them from a triplet ground state, 3Σg, into an excited singlet state, 1Δg, which has an excitation energy of 94 kJ mol−1. Once in the excited singlet state, the oxygen presents an extremely active species, which reacts chemically with the surrounding cell material and causes tumor apoptosis.
The use of longer wavelength, near-infrared, light to cause absorption of two photons of longer wavelength light has been developed to treat breast and other cancers. See U.S. Pat. Nos. 5,829,448, 5,832,931, 5,998,597, and 6,042,603. This two-photon technique employs a mode-locked Ti:sapphire laser to administer PDT with near-infrared light. In contrast to one-photon PDT, the near-infrared light produced by the Ti:sapphire laser is at a wavelength substantially longer than the characteristic one-photon absorption waveband of the photoreactive agent employed. Instead of the single photon absorption process involved in a conventional photodynamic reaction, a two photon process may occur upon radiation with a pulse of the 700-1300 nm light. Due to its relatively long wavelength, the near-infrared light emitted by a Ti:sapphire laser can penetrate into tissue up to 8 centimeter or more, making it possible to treat tumors that are relatively deep within a subject's body, well below the dermal layer.
For photosensitizer molecules to be particularly efficacious they should selectively accumulate in the tumor tissue. It is known that porphyrin-based molecules possess this feature. To date, the U.S. Food and Drug Administration has approved at least two porphyrin-based PDT agents: Photofrin®, and Verteporfrin®. Photofrin® is a naturally occurring porphyrin, which absorbs light in the visible spectral range (λ<690 nm). However, neither of these compounds have significant absorption spectra in the near-infrared region of radiation of 700 to 1300 nm, nor do they exhibit efficient multi-photon absorption.
Chemical modification of the porphyrin structure, such as to chlorin or bacteriochlorin, to shift the one-photon absorption band to longer wavelengths is limited by the fundamental requirement that the energy of the T1 state be higher than the excitation energy of singlet oxygen. Furthermore, such structural modification of the porphyrin structure may result in a less stable compound.
Non-porphyrin-based materials may have enhanced TPA cross-sections but typically lack either the ability to generate singlet oxygen, or have either unknown or deleterious interaction properties with biological tissue.
Thus, there is a need of porphyrin-based materials which safely interact with biological tissue and exhibit both a significant two-photon absorption cross-section for radiation in the near-infrared region and the ability to generate singlet oxygen. There is also a need to effectively treat tumors and other manifestations of disease located deep within a subject's body by PDT. Presently known and approved PDT agents require the use of radiation ranging from about 620 nm to 690 nm. This range of radiation typically penetrates most tissues to a depth of no more than a few millimeters.